PART X SPECIAL TOPICS

59
C H A P T E R

Drugs Used in
Gastrointestinal Disorders

The gastrointestinal tract serves many important functions: Some of these drugs have been discussed previously. This chapter
digestive, excretory, endocrine, exocrine, and so on. These mentions them and discusses in more detail others that do not
functions are the targets of several important classes of drugs. fall into the classes of agents described previously.

Drugs used for gastrointestinal disorders

Drugs for
Motility Drugs for irritable Drugs for Other Antiemetics
acid-peptic
promoters bowel syndrome inflammatory agents
disease
bowel disease

Metoclopramide, Anticholinergics, 5-ASA drugs, Pancreatic lipase,

cholinomimetics serotonin antagonists corticosteroids laxatives,
immunosuppresants, antidiarrheals
anti-TNF drugs ursodiol

H2 Proton pump Mucosal protective

Antacids Antibiotics
blockers inhibitors agents (sucralfate,
(cimetidine) (omeprazole) misoprostol,
bismuth compounds)

5-HT3 blockers D2 blockers H1 blockers Antimuscarinics Corticosteroids Cannabinoids Neurokinin receptor

(ondansetron) (prochlorperazine) (diphenhydramine) (scopolamine) (dexamethasone) (dronabinol) antagonists
(aprepitant)

483
484 PART X Special Topics

High-Yield Terms to Learn

Acid-peptic disease A group of disorders involving erosion or ulceration of the mucosal lining of the gastrointestinal
tract; includes GERD, gastric and duodenal ulcers, nonulcer dyspepsia, and stress-related gastritis
Antiemetic A drug that reduces nausea and vomiting
Gastroesophageal reflux Esophageal irritation or inflammation due to reflux of stomach acid; also known as heartburn
disease (GERD)
Gastroparesis Paralysis of the muscles of the stomach and possibly other parts of the gastrointestinal tract due
to damage to gastrointestinal nerves or muscle; common in advanced diabetes and advanced
Parkinsons disease
Inflammatory bowel Inflammatory disorder involving irritation and ulceration of the colon and rectum (ulcerative colitis)
disease (IBD) or the colon plus more proximal parts of the gastrointestinal tract (Crohns disease)
Irritable bowel syndrome Disease of unknown origin characterized by episodes of abdominal discomfort and abnormal bowel
(IBS) function (diarrhea, constipation, or both)
Prokinetic A drug that promotes gastrointestinal motility
Proton pump The parietal cell H+/K+ ATPase that uses the energy of ATP to secrete protons into the stomach
(Figure 591); final common target of drugs that suppress acid secretion

A. Drugs Used in Acid-Peptic Diseases
Ulceration and erosion of the lining of the upper portion of
the gastrointestinal tract are common problems that manifest as
gastroesophageal reflux disease (GERD), gastric and duodenal
peptic ulcers, and stress-related mucosal injury. Drugs used in
acid-peptic disease reduce intragastric acidity by manipulating
systems controlling acid secretion (Figure 591), promote muco-
sal defense or, in the case of peptic ulcers, eradicate the bacterium
Helicobacter pylori, which is detectable in over 80% of patients
with duodenal ulcers.
1. AntacidsAntacids are weak bases that neutralize stomach
acid by reacting with protons in the lumen of the gut and may also
stimulate the protective functions of the gastric mucosa. When
used regularly in the large doses needed to significantly raise the
stomach pH, antacids reduce the recurrence rate of peptic ulcers.
The antacids differ mainly in their absorption and effects on
stool consistency. Popular antacids include magnesium hydroxide
(Mg[OH]2) and aluminum hydroxide (Al[OH]3). Neither of these
weak bases is significantly absorbed from the bowel. Magnesium
hydroxide has a strong laxative effect, whereas aluminum hydroxide
has a constipating action. These drugs are available as single-ingre-
dient products and as combined preparations. Calcium carbonate
and sodium bicarbonate are also weak bases, but they differ from
aluminum and magnesium hydroxides in being absorbed from the
gut. Because of their systemic effects, calcium and bicarbonate salts
are less popular as antacids.
2. H2-receptor antagonistsCimetidine and other H2 antag-
onists (ranitidine, famotidine, and nizatidine) inhibit stomach
acid production, especially at night. They are effective in the
treatment of GERD, peptic ulcer disease, and nonulcer dyspepsia
and in the prevention of stress-related gastritis in seriously ill
patients. Although they are still used widely, their clinical use is
being supplanted by the more effective and equally safe proton
pump inhibitors. The H2 antagonists are described in detail in
Chapter 16.
3. Proton pump inhibitorsOmeprazole and other proton pump
inhibitors (esomeprazole, (dex)lansoprazole, pantoprazole, and
rabeprazole) are lipophilic weak bases that diffuse into the
parietal cell canaliculi, where they become protonated and con-
centrated more than 1000-fold. There they undergo conversion
to compounds that irreversibly inactivate the parietal cell H+/K+
ATPase, the transporter that is primarily responsible for produc-
ing stomach acid. Oral formulations of these drugs are enteric
coated to prevent acid inactivation in the stomach. After absorption
in the intestine, they are rapidly metabolized in the liver, with
half-lives of 12 h. However, their durations of action are approxi-
mately 24 h, and they may require 34 d of treatment to achieve
their full effectiveness.
Proton pump inhibitors are more effective than H2 antagonists
for GERD and peptic ulcer and equally effective in the treatment
of nonulcer dyspepsia and the prevention of stress-related muco-
sal bleeding. They are also useful in the treatment of Zollinger-
Ellison syndrome. Adverse effects of proton pump inhibitors
occur infrequently and include diarrhea, abdominal pain, and
headache. Chronic treatment with proton pump inhibitors may
result in hypergastrinemia. However, there is no documentation
that the use of these drugs increases the incidence of carcinoid or
colon cancer. Proton pump inhibitors may decrease the oral bio-
availability of vitamin B12 and certain drugs that require acidity
for their gastrointestinal absorption (eg, digoxin, ketoconazole).
Patients taking proton pump inhibitors may have a small increase
in the risk of respiratory and enteric infections.
4. SucralfateAn aluminum sucrose sulfate, sucralfate is
a small, poorly soluble molecule that polymerizes in the acid
 CHAPTER 59 Drugs Used in Gastrointestinal Disorders 485

Fundus of stomach

Vagus Fundic blood vessel

preganglionic
nerve

+ Gastrin

Vagus G/CCK-B-R
preganglionic +
M3-R
nerve

Histamine
ECL
cell
Antrum blood vessel

ACh Histamine

+ + + Gastrin

+
ACh-R M3-R H2-R G/CCk-B-R
GRP-R
Gastrin

Parietal cell
Somatostatin-R Somatostatin

H+/K+
G cell D cell
ATPase
+ K+ K+

+ H+ H+ H+ H+
Dietary peptides Luminal acid H+ H+
Luminal acid
Lumen of antrum Lumen of fundus

FIGURE 591 Schematic model of physiologic control of hydrogen ion (acid) secretion by the gastric parietal cells, which are stimulated
by gastrin (acting on gastrin/CCK-B receptors), acetylcholine (ACh; M3 receptor), and histamine (H2 receptor). Acid is secreted across the parietal
cell canalicular membrane by the H+/K+ ATPase proton pump into the gastric lumen. The gastrin that is secreted by antral G cells in response
to intraluminal dietary peptides acts directly on parietal cells and also stimulates release of histamine from enterochromaffin-like (ECL) cells.
The vagus nerve stimulates postganglionic neurons of the enteric nervous system to release ACh, which acts on parietal and ECL cells. In the
antrum, release of gastrin-releasing peptide (GRP) from postganglionic neurons directly increases gastrin release, whereas release of ACh indi-
rectly increases gastrin secretion by inhibiting release of somatostatin from antral D cells. The increase in intraluminal H+ concentration causes D
cells to release somatostatin and thereby inhibit gastrin release from G cells. CCK, cholecystokinin; R, receptor. (Reproduced, with
permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 621.)

environment of the stomach. The polymer binds to injured tissue
and forms a protective coating over ulcer beds. Sucralfate acceler-
ates the healing of peptic ulcers and reduces the recurrence rate.
Unfortunately, sucralfate must be taken 4 times daily. Sucralfate
is too insoluble to have significant systemic effects when taken by
the oral route; toxicity is very low.
5. MisoprostolAn analog of PGE1, misoprostol increases
mucosal protection and inhibits acid secretion. It is effective in
reducing the risk of ulcers in users of nonsteroidal anti-inflamma-
tory drugs (NSAIDs) but is not widely used because of the need
for multiple daily dosing and poorly tolerated adverse effects (gas-
trointestinal upset and diarrhea). Misoprostol is discussed further
in Chapter 18.
6. Colloidal bismuthBismuth has multiple actions, including
formation of a protective coating on ulcerated tissue, stimulation
of mucosal protective mechanisms, direct antimicrobial effects,
and sequestration of enterotoxins. Bismuth subsalicylate, a non-
prescription formulation of bismuth and salicylate, reduces stool
frequency and liquidity in infectious diarrhea. Bismuth causes
black stools.
7. AntibioticsChronic infection with H pylori is present in
most patients with recurrent non-NSAID-induced peptic ulcers.
Eradication of this organism greatly reduces the rate of recur-
rence of ulcer in these patients. One regimen of choice consists
of a proton pump inhibitor plus a course of clarithromycin and
amoxicillin (or metronidazole in patients with penicillin allergy).
486 PART X Special Topics
B. Drugs That Promote Upper Gastrointestinal Motility
Prokinetic drugs that stimulate upper gastrointestinal motility
are helpful for gastroparesis and for postsurgical gastric emptying
delay. Their ability to increase lower esophageal sphincter pres-
sures also makes them useful for some patients with GERD. In the
past, cholinomimetic agonists such as bethanechol were used for
GERD and gastroparesis, but the availability of less toxic agents
has supplanted their use. The acetylcholinesterase inhibitor neo-
stigmine is still used for the treatment of hospitalized patients with
acute large bowel distention. The cholinomimetics are discussed
in Chapter 7.
In the enteric nervous system, dopamine inhibits cholinergic
stimulation of smooth muscle contraction. Metoclopramide and
domperidone are D2 dopamine receptor antagonists that pro-
mote gastrointestinal motility. The D2 receptor-blocking action
of these drugs in the area postrema is also of value in preventing
emesis after surgical anesthesia and emesis induced by cancer
chemotherapeutic drugs. When used chronically, metoclopramide
can cause symptoms of parkinsonism, other extrapyramidal effects,
and hyperprolactinemia. Because it does not cross the blood-brain
barrier, domperidone is less likely to cause CNS toxicity.
The macrolide antibiotic erythromycin (Chapter 44) promotes
motility by stimulating motilin receptors. It may have benefit in
some patients with gastroparesis.
C. Laxatives
Laxatives increase the probability of a bowel movement by several
mechanisms: an irritant or stimulant action on the bowel wall; a
bulk-forming action on the stool that evokes reflex contraction of the
bowel; a softening action on hard or impacted stool; and a lubricat-
ing action that eases passage of stool through the rectum. Examples
of drugs that act by these mechanisms are listed in Table 591.
D. Antidiarrheal Agents
The most effective antidiarrheal drugs are the opioids and deriva-
tives of opioids that have been selected for maximal antidiarrheal
and minimal CNS effect. Of the latter group, the most important
TABLE 591 The major laxative mechanisms and
some representative laxative drugs.
Mechanism Examples
Bulk-forming Psyllium, methylcellulose, polycarbophil
Stool-softening Docusate, glycerin, mineral oil
Osmotic Magnesium oxide, sorbitol, lactulose, magnesium
citrate, sodium phosphate, polyethylene glycol
Stimulant Aloe, senna, cascara, castor oil, bisacodyl
Chloride channel Lubiprostone
activator Linaclotide (indirect via cGMP)
Opioid receptor Methylnaltrexone, alvimopan
antagonists
are diphenoxylate and loperamide, meperidine analogs with very
weak analgesic effects. Diphenoxylate is formulated with antimus-
carinic alkaloids (eg, atropine) to reduce the likelihood of abuse;
loperamide is formulated alone. Kaolin, a naturally occurring
hydrated magnesium aluminum silicate, is combined with pectin,
an indigestible carbohydrate derived from apples in a popular
nonprescription preparation that absorbs bacterial toxins and
fluid, resulting in decreased stool liquidity. They can cause consti-
pation and interfere with absorption of other drugs. Antidiarrheal
agents may be used safely in patients with mild to moderate acute
diarrhea. However, these agents should not be used in patients
with bloody diarrhea, high fever, or systemic toxicity because of
the risk of worsening the underlying condition.
E. Drugs Used for Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is associated with recurrent episodes
of abdominal discomfort (pain, bloating, distention, or cramps)
plus diarrhea or constipation (or both). The pharmacologic strat-
egy is tailored to patients symptoms and includes antidiarrheal
agents and laxatives, and for the treatment of abdominal pain,
low doses of tricyclic antidepressants (Chapter 30). The anticho-
linergic drugs dicyclomine and hyoscyamine are used as anti-
spasmodics to relieve abdominal pain; however, their efficacy has
not been convincingly demonstrated. Alosetron, a potent 5-HT3
antagonist, is approved for treatment of women with severe IBS
with diarrhea. Alosetron can cause constipation, including rare
complications of severe constipation that have required hospi-
talization or surgery, and rare cases of ischemic colitis. For this
reason, its use is restricted. Lubiprostone, a laxative that activates
the type 2 chloride channels in the small intestine, is approved for
treatment of women with IBS with predominant constipation.
Linaclotide has a similar therapeutic effect but acts more indirectly:
It binds to and activates guanylyl cyclase-C on the luminal intes-
tinal epithelial surface, resulting in increased intracellular and
extracellular cGMP, which in turn leads to activation of the type 2
chloride channels.
F. Drugs With Antiemetic Actions
A variety of drugs are valuable in the prevention and treatment
of vomiting, especially cancer chemotherapy-induced vomiting.
In addition to metoclopramide and other D2 dopamine receptor
antagonists, useful antiemetics are drugs with H1 histamine-
blocking activity including diphenhydramine (Chapter 16), and
several phenothiazines (Chapter 29); antimuscarinic drugs such
as scopolamine (Chapter 8); the corticosteroid dexamethasone
(Chapter 39); and the cannabinoid receptor agonists dronabinol
and nabilone (Chapter 32). The 5-HT3 antagonists (Chapter 16)
ondansetron, granisetron, dolasetron, and palonosetron are
particularly useful in preventing nausea and vomiting after general
anesthesia and in patients receiving cancer chemotherapy. Apre-
pitant, a newer antiemetic, is an antagonist of the neurokinin 1
(NK1) receptor, a receptor in the area postrema of the CNS that is
activated by substance P and other tachykinins (see Chapter 17).
Aprepitant is approved for use in combination with other anti-
emetics for prevention of the nausea and vomiting associated with
 CHAPTER 59 Drugs Used in Gastrointestinal Disorders 487

highly emetogenic chemotherapeutic regimens. Aprepitant can Disease Responsiveness

cause fatigue, dizziness, and diarrhea. As a substrate and an inhibi- severity Therapy to therapy
tor of CYP3A4, aprepitant participates in many drug interactions.
Surgery
Natalizumab
Severe Cyclosporine Refractory
SKILL KEEPER: 5-HT AGONISTS AND TNF antagonists
Intravenous corticosteroids
ANTAGONISTS (SEE CHAPTERS 16 AND 30)
TNF antagonists
List the various 5-HT receptor agonists and antagonists in Oral corticosteroids
Moderate
current use. Describe their clinical applications. Methotrexate
The Skill Keeper Answer appears at the end of the chapter. Azathioprine / 6-Mercaptopurine

G. Drugs Used in Inflammatory Bowel Disease (IBD)
1. AminosalicylatesDrugs containing 5-aminosalicylic acid
(5-ASA) are used as topical therapy for IBD. The precise mecha-
nism of 5-ASA action is uncertain but may involve inhibiting
the synthesis of prostaglandins and inflammatory leukotrienes,
and interfering with the production of inflammatory cytokines.
5-ASA, known generically as mesalamine, is readily absorbed from
the small intestine whereas absorption from the colon is extremely
low. Proprietary coated formulations of 5-ASA (Pentasa, Asacol,
Lialda) deliver 5-ASA to different segments of the small and large
intestine (Figure 592). Balsalazide, olsalazine, and sulfasala-
zine contain 5-ASA bound by an azo (N=N) bond to an inert
compound, another 5-ASA molecule, or sulfapyridine. The azo
structure is poorly absorbed in the small intestine. Sulfasalazine
(a combination of 5-ASA and sulfapyridine) has a higher inci-
dence of adverse effects than the other 5-ASA drugs, due to the
systemic absorption of the sulfapyridine moiety. These effects are
dose related and include nausea, gastrointestinal upset, headaches,
arthralgias, myalgias, bone marrow suppression, malaise, and
severe hypersensitivity reactions. Other aminosalicylates, which
do not contain sulfapyridine, are well tolerated.
2. Other agentsOther drugs used in the treatment of
ulcerative colitis and Crohns disease (Figure 593) include
antibiotics, glucocorticoids (eg, budesonide; Chapters 39
Budesonide (ileitis)
Topical corticosteroids (proctitis)
Mild Antibiotics Responsive
5-Aminosalicylates
FIGURE 593 Therapeutic pyramid approach to inflammatory
bowel disease. Treatment choice is predicated on both the severity
of the illness and responsiveness to therapy. Agents at the bottom
of the pyramid are less efficacious but carry a lower risk of serious
adverse effects. TNF, tumor necrosis factor. (Reproduced, with
permission, from Katzung BG, editor: Basic & Clinical Pharmacology,
12th ed. McGraw-Hill, 2012: Fig. 629.)
and 55), immunosuppressive antimetabolites (eg, azathioprine,
6-mercaptopurine, methotrexate; Chapters 54 and 55), anti-
tumor necrosis factor [TNF] drugs (eg, infliximab, adalimumab,
golimumab; Chapters 36 and 55). Natalizumab is a humanized
monoclonal antibody that blocks integrins on circulating leuko-
cytes. Because of a possible association of natalizumab with multi-
focal leukoencephalopathy, it is carefully restricted to patients with
severe refractory Crohns disease.
H. Pancreatic Enzyme Replacements
Steatorrhea, a condition of decreased fat absorption together with
an increase in stool fat excretion, results from inadequate pancre-
atic secretion of lipase. The abnormality of fat absorption can be
significantly relieved by oral administration of pancreatic lipase
(pancrelipase or pancreatin) obtained from pigs. Pancreatic

Stomach Small Intestine Colon

Jejunum Ileum Proximal Distal Rectum
5-ASA delayed release capsules (Pentasa)

5-ASA pH-dependent release (Asacol, Lialda)

Sulfasalazine

Balsalazide

5-ASA enema (Rowasa)

5-ASA suppository (Canasa)

FIGURE 592 Sites of 5-aminosalicylic acid (5-ASA) release from different formulations in the small and large intestines. (Reproduced, with
permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 627.)
488 PART X Special Topics

lipase is inactivated at a pH lower than 4.0; the enzyme should 5. A 34-year-old woman has irritable bowel syndrome with
be taken as enteric-coated capsules unless the pH is raised with diarrhea that is not responsive to conventional therapies.
antacids or drugs that reduce acid secretion. Despite the small risk of severe constipation and ischemic
colitis, the patient decides to begin therapy with alosetron.
Alosetron has which of the following receptor actions?
I. Drugs That Inhibit the Formation of Gallstones (A) 5-HT3 receptor antagonist
The formation of cholesterol gallstones can be inhibited by the bile (B) 5-HT4 receptor agonist
acid derivative ursodiol, which decreases the cholesterol content of (C) D2 receptor antagonist
bile by decreasing hepatic cholesterol secretion and has other effects (D) NK1 receptor antagonist
on hepatocyte canalicular membranes. Toxicity due to the drug is (E) Muscarinic receptor antagonist
uncommon. 6. On your way to an examination, you experience the vulner-
able feeling that an attack of diarrhea is imminent. If you
stopped at a drugstore, which one of the following antidi-
QUESTIONS arrheal drugs could you buy without a prescription even
though it is related chemically to the strong opioid analgesic
1. A 55-year-old woman with type 1 diabetes of 40 years dura- meperidine?
tion complains of severe bloating and abdominal distress, (A) Aluminum hydroxide
especially after meals. Evaluation is consistent with diabetic (B) Diphenoxylate
gastroparesis. Which of the following is a prokinetic drug that (C) Loperamide
could be used in this situation? (D) Magnesium hydroxide
(A) Alosetron (E) Metoclopramide
(B) Cimetidine
(C) Loperamide 7. A 45-year-old man with a duodenal ulcer was treated with a
(D) Metoclopramide combination of drugs intended to heal the mucosal damage
(E) Sucralfate and to eradicate Helicobacter pylori. Which of the following
antibacterial drugs is used commonly to eradicate intestinal
2. A patient who is taking verapamil for hypertension and angina H pylori?
has become constipated. Which of the following drugs is (A) Cefazolin
an osmotic laxative that could be used to treat the patients (B) Ciprofloxacin
constipation? (C) Clarithromycin
(A) Aluminum hydroxide (D) Clindamycin
(B) Diphenoxylate (E) Vancomycin
(C) Magnesium hydroxide
(D) Metoclopramide 8. A patient is receiving highly emetogenic chemotherapy for
(E) Ranitidine metastatic carcinoma. To prevent chemotherapy-induced
nausea and vomiting, she is likely to be treated with which of
3. A 40-year-old male CEO came to the emergency department the following?
with severe burning chest pain radiating into his neck. His (A) Levodopa
electrocardiogram was normal and test for troponin was nega- (B) Methotrexate
tive. A diagnosis of GERD was made and he was sent home (C) Misoprostol
with a prescription for a drug that inhibits stomach acid. (D) Ondansetron
Which of the following is a drug that irreversibly inhibits the (E) Sucralfate
H+/K+ ATPase in the parietal cells?
(A) Cimetidine Questions 9 and 10. The following matching questions consist
(B) Diphenoxylate of a list of lettered options followed by several numbered items.
(C) Esomeprazole
For each numbered item, select the ONE option that is most
(D) Metoclopramide
(E) Sulfasalazine closely associated with it.
(A) Aluminum hydroxide
4. Which drug is most likely to be useful in the treatment of (B) Balsalazide
inflammatory bowel disease? (C) Castor oil
(A) Diphenhydramine (D) Cimetidine
(B) Diphenoxylate (E) Dexamethasone
(C) Mesalamine (F) Methotrexate
(D) Ondansetron (G) Metoclopramide
(E) Ursodiol (H) Mineral oil
(I) Omeprazole
(J) Linaclotide
(K) Pancrelipase
(L) Sucralfate
 CHAPTER 59 Drugs Used in Gastrointestinal Disorders 489

9. Which drug stimulates chloride secretion into the gut lumen
and is used for irritable bowel syndrome?
10. This is a small molecule that polymerizes in stomach acid
and coats the ulcer bed, resulting in accelerated healing and
reduction of symptoms.
ANSWERS
1. Of the drugs listed, only metoclopramide is considered a
prokinetic agent (ie, one that increases propulsive motility in
the gut). The answer is D.
10. Sucralfate is a small molecule that polymerizes in stomach
2. A laxative that mildly stimulates the gut would be most suit-
able in a patient taking a smooth muscle relaxant drug such
as verapamil. By holding water in the intestine, magnesium
hydroxide provides additional bulk and stimulates increased
contractions. A helpful mnemonic is magnesium magnifies
stool, aluminum hALts the stool. The answer is C.
3. Esomeprazole, the (S) isomer of omeprazole, is a prodrug convert-
ing spontaneously in the parietal cell canaliculus to a sulfonamide
that irreversibly inactivates the proton pump. The answer is C.
4. Mesalamine is a form of 5-aminosalicylic acid that is active
in the large intestine and thereby provides a local anti-
inflammatory effect that is useful in inflammatory bowel
disease. The answer is C.
5. Serotonin plays a major regulatory role in the enteric nervous
system, and the potent 5-HT3 receptor antagonist alosetron has
shown efficacy in treating women with IBS that is accompanied
by diarrhea. The answer is A.
6. Aluminum hydroxide is constipating but is not related
chemically to meperidine; magnesium hydroxide is a strong
laxative. The 2 antidiarrheal drugs that are structurally related
to opioids are diphenoxylate and loperamide. Loperamide is
available over-the-counter; diphenoxylate is mixed with atro-
pine alkaloids, and the product (Lomotil, others) requires a
prescription. The answer is C.
7. The macrolide antibiotic clarithromycin is commonly used in
antibiotic regimens designed to treat duodenal ulcers caused
by H pylori. The other antibiotics that are used include
amoxicillin, tetracycline, and metronidazole. Bismuth also
has an antibacterial action. The answer is C.
8. The 5-HT3 receptor antagonists are highly effective at pre-
venting chemotherapy-induced nausea and vomiting, which
can be a dose-limiting toxicity of anticancer drugs. The
answer is D.
9. Linaclotide is approved for the treatment of chronic consti-
pation and IBS with predominant constipation. Linaclotide
activates guanylyl cyclase-C on the luminal intestinal epithelial
surface, which leads to activation of the cystic fibrosis trans-
membrane conductance regulator (CFTR) leading to increased
chloride-rich secretion and acceleration of intestinal transit.
The answer is J.
acid and forms a protective coat over the ulcer bed. The
answer is L.
SKILL KEEPER ANSWER: 5-HT AGONISTS &
ANTAGONISTS (SEE CHAPTERS 16 AND 30)
The only serotonin agonists in common use are the 5-HT1D-
selective agonists such as sumatriptan and its congeners
(see Chapter 16) that are used in migraine. Ergot alkaloids
are partial agonists at several 5-HT receptors and are also
used in migraine and other conditions. Several valuable anti-
depressants are inhibitors of the serotonin reuptake pump
in neurons (see Chapter 30). Serotonin antagonists include
cyproheptadine (also an H1 blocker), phenoxybenzamine
(also an a blocker), and several of the atypical antipsychotic
drugs (eg, olanzapine, aripiprazole; see Chapter 29), which
have high affinity for HT2A receptors. Cyproheptadine is used
for pruritus and sometimes for carcinoid tumor. Phenoxyben-
zamine is used for carcinoid tumor as well as for pheochro-
mocytoma. 5-HT3 receptors are blocked by ondansetron and
its congeners. These drugs are extremely useful in preventing
postoperative and cancer chemotherapy-induced nausea and
vomiting.

CHECKLIST

When you complete this chapter, you should be able to:

Identify 5 different groups of drugs used in peptic ulcer disease.
Describe the mechanism of action of omeprazole and related drugs.
List 7 different drugs used in the prevention of chemotherapy- or radiation-induced
emesis and identify the receptors with which they interact.
Describe the mechanism of action, clinical uses, and adverse effects of metoclopramide.
Identify 2 drugs commonly used as antidiarrheal agents and 4 drugs with different
mechanisms that are used as laxatives.
Identify drugs used in the management of inflammatory bowel disease and irritable
bowel syndrome.
490 PART X Special Topics

DRUG SUMMARY TABLE: Gastrointestinal Drugs

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions

Drugs used in acid-peptic diseases

Proton pump inhibitors Irreversible blockade of Peptic ulcer, GERD, Half-lives much shorter Low toxicity reduction of
(PPIs; eg, omeprazole) H+/K+ ATPase in active erosive gastritis than duration of action stomach acid may reduce
gastric parietal cells absorption of some drugs
and increase that of others
Other PPIs: esomeprazole, dexlansoprazole, lansoprazole, pantoprazole, rabeprazole

H2-receptor blockers: cimetidine, famotidine, nizatidine, ranitidine reduce nocturnal acid but less effective than PPIs against stimulated secretion; very
safe, available over the counter (OTC). Cimetidine, but not other H2 blockers, is a weak antiandrogenic agent and a potent P450 enzyme inhibitor

Sucralfate: polymerizes at site of tissue damage and protects against further damage; very insoluble with no systemic effects; must be given
4 times daily
Antacids: popular OTC medication for symptomatic relief of heartburn; not as useful as PPIs and H2 blockers in peptic diseases

Prokinetic agents
Metoclopramide D2 receptor blocker Gastric paresis (eg, in Oral and parenteral Parkinsonian symptoms due
increases gastric empty- diabetes) antiemetic formulations to block of CNS D2 receptors
ing and intestinal motility
Domperidone: like metoclopramide but less CNS effect; not available in United States
Cholinomimetics: neostigmine used for colonic pseudo-obstruction in hospitalized patients
Macrolides: erythromycin useful in diabetic gastroparesis but tolerance develops

Laxatives
Magnesium hydroxide, Osmotic agents increase Simple constipation Oral Magnesium may be
other nonabsorbable water content of stool bowel prep for endos- absorbed and cause toxicity
salts and sugars copy (especially PEG in renal impairment
solutions)
Bulk-forming: methylcellulose, psyllium, etc; increase volume, stimulate evacuation
Stool surfactants: docusate, mineral oil; lubricate stool, ease passage
Stimulants: senna, cascara; stimulate activity; may cause cramping

Chloride channel activators: lubiprostone, a prostanoic acid derivative, stimulates chloride secretion into intestine, increasing fluid content;
linaclotide, guanylyl cyclase-C agonist, stimulates chloride secretion by CFTR
Opioid receptor antagonists: alvimopan, methylnaltrexone, block intestinal opioid receptors but do not enter CNS, so analgesia is maintained

Antidiarrheal drugs
Loperamide Activates opioid receptors Nonspecific, noninfec- Oral Mild cramping but little or
in enteric nervous system tious diarrhea no CNS toxicity
and slows motility with
negligible CNS effects

Diphenoxylate: similar to loperamide, but high doses can cause CNS opioid effects and toxicity

Colloidal bismuth compounds: subsalicylate and citrate salts available as OTC products; adsorption of toxins has some value in travelers diarrhea
Kaolin + pectin: adsorbent compounds available OTC in some countries

Drugs for irritable bowel syndrome (IBS)

Alosetron 5-HT3 receptor antagonist Severe diarrhea- Oral Rare but serious
of high potency and predominant IBS in constipation; ischemic
duration of binding women colitis bowel infarction
reduces smooth muscle
activity in GI tract
Anticholinergics: nonselective action on GI activity; associated with typical antimuscarinic toxicity
Chloride channel activator: lubiprostone is useful in constipation-predominant IBS in women

(Continued)
 CHAPTER 59 Drugs Used in Gastrointestinal Disorders 491

DRUG SUMMARY TABLE: Gastrointestinal Drugs (Continued)

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions

Antiemetics
5-HT3 antagonists 5-HT3 receptor block in GI Prevention of Oral and parenteral May slow colonic transit
(eg, ondansetron) and CNS chemotherapy-induced formulations
and postoperative nausea
and vomiting
Other 5-HT3 antagonist antiemetics: dolasetron, granisetron, palonosetron; see Chapter 16
Corticosteroids: mechanism not known but useful in antiemetic IV cocktails; see Chapter 39
Antimuscarinics (eg, scopolamine): effective in emesis due to motion sickness; no other types; see Chapter 8
Phenothiazines: act primarily through block of D2 and muscarinic receptors; see Chapter 29

Cannabinoids: dronabinol is available for use in chemotherapy-induced nausea and vomiting, but is associated with CNS marijuana effects
(see Chapter 32)

Aprepitant: A neurokinin 1 (NK1) antagonist available for use in chemotherapy-induced nausea and vomiting; associated with fatigue, dizziness,
diarrhea, and P450 interactions

Drugs for inflammatory bowel disease (IBD)

Mesalamine Mechanism uncertain, Mild to moderately severe Various formulations Little or no toxicity
(5-aminosalicylate) may be inhibition of Crohns disease and designed to deliver drug
eicosanoid inflammatory ulcerative colitis to distal ileum and colon
mediators

Azo compounds: balsalazide, olsalazine, sulfasalazine; colonic bacterial azoreductase enzymes release 5-aminosalicylate in the colon; sulfasalazine
can cause sulfonamide toxicity due to absorption of the sulfapyridine moiety
Glucocorticoids: see Chapters 39 and 55
Immunosuppressant antimetabolites: see Chapters 54 and 55
Anti-TNF drugs: see Chapters 36 and 55
Natalizumab: antibody that blocks leukocyte integrins; may cause multifocal leukoencephalopathy

Pancreatic supplements
Pancrelipase Replacement enzymes Pancreatic insufficiency Taken with every meal May increase incidence of
from animal pancreatic due to cystic fibrosis, gout
extracts that improve pancreatitis,
digestion of fat, protein, pancreatectomy
and carbohydrate
Pancreatin: similar pancreatic extracts but much lower potency; rarely used

Bile acid therapy for gallstones

Ursodiol Reduces cholesterol Gallstones in patients Oral Little or no toxicity
secretion into bile refusing or not eligible for
surgery

GERD, gastrointestinal reflux disease; PEG, pegylated.